A Method for the Tensile Strength Prediction of Tablets with Differing Powder Plasticities.

Tablets are the most commonly used dosage form in the pharmaceutical industry, and their properties such as disintegration, dissolution, and portability are influenced by their strength. However, in industry, the mixing fraction of powders to obtain a tablet compact with sufficient strength is determined based on empirical rules. Therefore, a method for predicting tablet strength based on the properties of a single material is required. The objective of this study was to quantitatively evaluate the relationship between the compression properties and tablet strength of powder mixtures. The compression properties of the powder mixtures with different plasticities were evaluated based on the force-displacement curves obtained from the powder compression tests. Heckel and compression energy analyses were performed to evaluate compression properties. During the compression energy analysis, the ratio of plastic deformation energy to elastic deformation energy (Ep/Ee) was assumed to be the plastic deformability of the powder. The quantitative relationship between the compression properties and tensile strength of the tablets was investigated. Based on the obtained relationship and the compression properties of a single material, a prediction equation was put forward for the compression properties of the powder mixture. Subsequently, a correlation equation for tablet strength was proposed by combining the values of K and Ep/Ee obtained from the Heckel and compression energy analyses, respectively. Finally, by substituting the compression properties of the single material and the mass fraction of the plastic material into the proposed equation, the tablet strength of the powder mixture with different plastic deformabilities was predicted.

Enhancement of cell membrane permeability by using charged nanoparticles and a weak external electric field.

Because the cell membrane is the main barrier of intracellular delivery, it is important to facilitate and control the translocation of extracellular compounds across it. Our earlier molecular dynamics simulations suggested that charged nanoparticles under a weak external electric field can enhance the permeability of the cell membrane without disrupting it. However, this membrane permeabilization approach has not been tested experimentally. This study investigated the membrane crossing of a model compound (dextran with a Mw of 3000-5000) using charged nanoparticles and a weak external electric field. A model bilayer lipid membrane was prepared by using a droplet contact method. The permeability of the membrane was evaluated using the electrophysiological technique. Even when the applied electric field was below the critical strength for membrane breakdown, dextran was able to cross the membrane without causing membrane breakdown. These results indicate that adding nanomaterials under a weak electric field may enhance the translocation of delivery compounds across the cell membrane with less damage, suggesting a new strategy for intracellular delivery systems.

Development of a Simple In-Die Method for Determination of Capping Tendency in Rotary Tableting Machines.

A rotary tableting machine is used for the continuous tableting process. Tableting conditions often result in capping, leading to serious problems during production. Several studies have been conducted to predict the tablet capping tendency. However, as most previous studies were conducted using a compaction simulator, there is a lack of technology that can be readily applied during actual production. Therefore, the present study aimed to develop a novel method for predicting tablet capping in a rotary tableting machine. We hypothesized that capping occurs when residual stress of the tablet inside a die exceeds the critical stress immediately before ejection. Residual stress was evaluated by measuring the in-line die-wall pressure in a rotary tableting machine. Additionally, critical stress was estimated from the tablet strength inside the die using the Rumpf's equation. The critical and residual stresses were compared to determine the capping tendency to some extent. The findings of this study will substantially contribute to the rapid detection of tablet capping during tablet production.

Mechanism of Solubility Enhancement of Poorly Water-Soluble Drugs Triggered by Zeolitic Imidazolate Frameworks.

Numerous efforts have been devoted to improving the solubility of poorly water-soluble drugs. Recently, it was reported that the use of metal-organic frameworks (MOFs), which are a new class of porous materials consisting of metal ions and organic ligands, is effective in improving the solubility of poorly water-soluble drugs. Our previous study demonstrated an improvement in the solubility of indomethacin (IDM) triggered by the zeolitic imidazolate framework-8 (ZIF-8). The present study aimed to elucidate the solubilization mechanism using the ZIF series, namely, ZIF-8, ZIF-67, and ZIF-L. It was confirmed that the solubility of ZIF-trapped IDM and ibuprofen (IBU) was enhanced compared to the raw drugs, regardless of the ZIF type. This study focused on 2-methylimidazole (2-MIM), which is commonly used as a ZIF organic ligand. Both IDM and IBU were easily dissolved by the addition of 2-MIM, suggesting that the presence of 2-MIM enhanced the solubility of the drugs. Inductively coupled plasma measurements also confirmed the presence of metal ions of ZIFs in the supernatant solution after the drug release tests, indicating the decomposition of ZIFs during drug release. The findings of this study demonstrated the solubilization mechanism of poorly water-soluble drugs using ZIF particles. We observed that the drugs loaded on the ZIFs were released simultaneously with the decomposition of some of the ZIFs. The 2-MIM molecules were also released concurrently. The presence of 2-MIM improved the solubility of poorly water-soluble drugs.

Direct translocation of a negatively charged nanoparticle across a negatively charged model cell membrane.

Nanoparticles have attracted much attention as a carrier for drug, gene, and macromolecule delivery in next-generation biomedical and therapeutic technologies. In delivery applications, nanoparticles tend to have negative charge due to the negative charge of biomolecules used as delivery cargo, while biological cell membranes are also negatively charged. This means that negatively charged nanoparticles (NC-NPs) are required to translocate across these negatively charged cell membranes (NC-CMs). However, this translocation is unlikely to occur because of electrostatic interactions. Here, we investigated the translocation of a NC-NP across a NC-CM under a transmembrane electric potential through coarse-grained molecular dynamics simulations. To model the transmembrane potential, two approaches were adopted: externally applied electric field and ionic charge imbalance. We showed that a NC-NP can directly translocate across a NC-CM via a non-disruptive pathway under a weak external electric field with an ionic charge imbalance. It was also found that the ionic charge imbalance contributes to the membrane crossing of a NC-NP as well as the self-resealing of the cell membrane after a NC-NP translocation. Our findings imply that NC-NPs can be delivered into a cell by combining applied electric field with membrane hyperpolarization/depolarization induced by an external stimulus.

Characterization of Tableting Speed-Dependent Deformation Properties of Active Pharmaceutical Ingredients in Powder Mixtures Using Out-of-Die Method.

A quantitative evaluation method for determining the effect of tableting speed on the compression properties of pharmaceutical powders was investigated in this study. Cilostazol and ibuprofen were used as active pharmaceutical ingredients (APIs) and mixed with lactose monohydrate and microcrystalline cellulose. Viscoelasticity was examined to evaluate the raw material, and stress relaxation tests were conducted to determine the apparent viscosity and elasticity coefficients of the placebo and two APIs. Tablets were prepared using a compaction simulator and a rotary tablet press at the tableting speeds ranging from laboratory to commercial. The in-die or out-of-die strain rate sensitivity (SRS) indices were determined as a measure of the compressibility and compactibility. The results showed that the sensitivity of the out-of-die SRS was higher than that of the in-die SRS. The out-of-die SRS of ibuprofen 20% powder, which showed high elasticity and low viscosity, was 13.3-47.9%, whereas that of the placebo and cilostazol 20% (w/w) powder was <7.5%. A peripheral speed difference of more than 300 mm/s during the out-of-die SRS was sensitive enough to detect the capping tendency. Cilostazol, which has lower elasticity and higher viscosity than ibuprofen, was tested using powder mixtures with the API concentrations of 5-40%; the compressibility SRS was <5% for all API concentrations. In contrast, the compressibility SRS of ibuprofen increased from 4.8 to 81% depending on the API concentration. Using the compressibility SRS as an index, it was possible to extract the tableting speed-dependent compressibility characteristics of API from the powder mixtures containing API.

Numerical Study on Spray Drying Process: Effect of Nonuniform Temperature Field and Interaction between Droplets on Evaporation Rates of Individual Droplets.

Spray drying process is widely used to produce particulate materials in the pharmaceutical industries, such as porous materials for direct compression, solid dispersion for improvement of drug dissolution properties, micro encapsulation to stabilize active compounds, taste masking, preparation of dry powder for inhalation. However, as many factors affect the physical properties of dried particles and the spray drying processes have complex behaviors in which heat and mass transfer occur simultaneously, the detailed mechanisms of dry particle generation have yet to be sufficiently elucidated. In this study, computational fluid dynamics was used to simulate water droplet evaporation in a spray dryer, and the evaporation kinetics of "individual droplets" in the droplet aggregate (group) were analyzed. The numerical simulation revealed that each droplet had different evaporation rates owing to the following two reasons. First, the driving force of evaporation, ΔT, changed every moment as the droplets traveled through different temperature fields in the drying tower. Second, it was calculated the driving force for droplet evaporation differed from the ideal system because the evaporation of other droplets changed the fluid characteristics around the droplets. The obtained results are important findings that lead to the understanding the spray drying process to design and manufacture the pharmaceutical products.

Numerical Study on Particle Adhesion in Dry Powder Inhaler Device.

This study investigated the particle adhesion mechanism in a capsule of dry powder inhaler (DPI) based on a combined computational fluid dynamics and discrete element method (CFD-DEM) approach. In this study, the Johnson-Kendall-Roberts (JKR) theory was selected as the adhesion force model. The simulation results corroborated the experimental results-numerous particles remained on the outlet side of the capsule, while a few particles remained on the inlet side. In the computer simulation, the modeled particles were placed in a capsule. They were quickly dispersed to both sides of the capsule, by air fed from one side of the capsule, and delivered from the air inlet side to the outlet side of the capsule. It was confirmed that vortex flows were seen at the outlet side of the capsule, which, however, were not seen at the inlet side. Numerous collisions were observed at the outlet side, while very few collisions were observed at the inlet side. These results suggested that the vortex flows were crucial to reduce the amount of residual particles in the capsule. The original capsule was then modified to enhance the vortex flow in the area, where many particles were found remaining. The modified capsule reduced the number of residual particles compared to the original capsule. This investigation suggests that the CFD-DEM approach can be a great tool for understanding the particle adhesion mechanism and improving the delivery efficiency of DPIs.

Direct translocation of nanoparticles across a model cell membrane by nanoparticle-induced local enhancement of membrane potential.

In biomedical technologies that use nanoparticles, the nanoparticles are often required to translocate across a cell membrane. Application of an external electric field has been used to increase the cell membrane permeability; however, damage to the cell is of great concern. Using a molecular dynamics simulation, we show that even under a weak external electric field that is lower than the membrane breakdown intensity, a cationic nanoparticle will directly translocate across a model cell membrane without membrane disruption. We then reveal its physical mechanism. At the contact interface between the nanoparticle and the cell membrane, the electric potential across the membrane is locally enhanced by superimposing the nanoparticle surface potential on the externally applied potential, resulting in its direct translocation. Our finding implies that, by controlling the nanoparticle-induced local enhancement of the membrane potential, the cellular delivery of nanoparticles via a non-endocytic and non-disruptive pathway can be realized.

Development of Universal Formulation with Superior Re-dispersion Using Nanocrystal Approach with Simultaneous Identification of API Physicochemical Properties.

Universal nanocrystal formulation which can be applied to water-insoluble compounds was proposed and the criteria of its physicochemical properties as an active pharmaceutical ingredients (API) were investigated. Nanocrystal suspension was prepared by a wet-beads milling method. An acceptable Critical Quality Attributes (CQA) of nanocrystal suspension was defined by Z-average less than 500 nm and Polydispersity index (PDI) less than 0.3. Screening studies of dispersing and wetting agents were conducted using three model compounds in different pKa, melting points, etc., to find universal nanocrystal formulation. The effect of four structurally different polymer species (hydroxypropyl cellulose (HPC), hydoroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA)) and their different grades or five different surfactants (docusate sodium (DOSS), sodium lauryl sulfate (SLS), cetyl trimethyl ammonium bromide (CTAB), polysolbate80 (PS80), and polyoxyethylene castor oil (CO-35)) were studied on the re-dispersion stability. It was found that the combination of 4% (w/v) HPC-SSL and 0.2% (w/v) DOSS was the most robust nanocrystal formulation owing to Z-average less than 200 nm and good re-dispersion stability without aggregates at pH 1.2 and pH 6.8. API physicochemical properties were also identified using ten water-insoluble compounds. Consequently, it was found that solubility (water, pH 1.2 and pH 6.8), molecular weight, hydrogen bonding acceptor and the ratio of log D7.4 to C Log P were critical factors.

Effect of Particle-Wall Interaction and Particle Shape on Particle Deposition Behavior in Human Respiratory System.

Dry powder inhalation (DPI) has attracted much attention as a treatment for respiratory diseases owing to the large effective absorption area in a human respiratory system. Understanding the drug particle motion in the respiratory system and the deposition behavior is necessary to improve the efficiency of DPI. We conducted computer simulations using a model coupling a discrete element method and a computational fluid dynamics method (DEM-CFD) to evaluate the particle deposition in human respiratory system. A simple artificial respiratory model was developed, which numerically investigated the effect of particle properties and inhalation patterns on the particle deposition behavior. The DEM-CFD simulations demonstrated that the smaller- and lower-density particles showed higher reachability into the simple respiratory model, and the particle arrival ratio to the deep region strongly depended on the aerodynamic diameter. The particle arrival ratio can be described as an exponential function of the aerodynamic diameter. Furthermore, the exponential relationship between the particle reachability into the depth of the simple respiratory model and the aerodynamic diameter predicted the particle aerodynamic diameter based on the required reachability. The particle shape also had an impact on the particle deposition behavior. The rod-like particles with a larger aspect ratio indicated higher reachability into the depth of the simple respiratory model. This was attributed to the high velocity motion of the particles whose long axis was in the direction of the deep region.

Analysis of Microstructure of Granules Prepared by Continuous Twin Screw Granulator Using X-Ray Micro-computed Tomography.

Granules prepared by a continuous twin screw granulator (TSG) were analyzed by X-ray micro-computed tomography (X-ray µCT) and the relationships between porosity of granules and granule properties were investigated. A model formulation containing ibuprofen, lactose monohydrate, microcrystalline cellulose, and hydroxypropyl cellulose was used. The porosity of granules was measured by X-ray µCT and mercury porosimetry. The data sets obtained by both methods showed linear correlation despite different values, which were attributed to the resolution of X-ray µCT and a low-signal-to-noise ratio of the original cross-sectional images. The porosity of granules measured by X-ray µCT decreased from 11-14 to 6-7% as liquid-to-solid ratio (L/S) increased, while the standard deviation (S.D.) of the porosity of individual granules decreased from 4-5 to 2%. L/S affected the porosity of granules. By contrast, the effect of screw speed was not significant. Pressure transmission, G, which indicates the liquid dispersion in wet kneaded masses, increased as the porosity of granules and the S.D. decreased. The cross-sectional images showed that granules were densified as L/S increased. Based on these results, the effect of L/S on the porosity of granules can be explained by liquid dispersion and densification of the wet granules. The porosity of granules measured by X-ray µCT showed good linear correlation with friability and drug dissolution rate (R2 = 0.9107 and 0.8834, respectively). This study revealed that the drug dissolution rate was regulated by a disintegration step in which the porosity of granules plays an important role.

Scale-Up of Lubricant Mixing Process by Using V-Type Blender Based on Discrete Element Method.

A method for scale-up of a lubricant mixing process in a V-type blender was proposed. Magnesium stearate was used for the lubricant, and the lubricant mixing experiment was conducted using three scales of V-type blenders (1.45, 21 and 130 L) under the same fill level and Froude (Fr) number. However, the properties of lubricated mixtures and tablets could not correspond with the mixing time or the total revolution number. To find the optimum scale-up factor, discrete element method (DEM) simulations of three scales of V-type blender mixing were conducted, and the total travel distance of particles under the different scales was calculated. The properties of the lubricated mixture and tablets obtained from the scale-up experiment were well correlated with the mixing time determined by the total travel distance. It was found that a scale-up simulation based on the travel distance of particles is valid for the lubricant mixing scale-up processes.

Development of a Novel Milling System Using Supercritical Carbon Dioxide for Improvement of Dissolution Characteristics of Water-Poorly Soluble Drugs.

The aim of this study is to develop a novel milling system using supercritical carbon dioxide (SC-CO2) for the improvement of dissolution characteristics of water-poorly soluble drugs. SC-CO2 possesses high potential in the application of nanotechnology, due to the attractive properties of SC-CO2 fluid such as cheap, inert and non-polluting. In addition, SC-CO2 has density comparable to a liquid, viscosity similar to a gas, and high diffusion capacity. Most of all, carbon dioxide exists as gas in room temperature and pressure, which enables the removal of fluid instantaneously. In this study, a novel method of milling using SC-CO2 was proposed to produce fine-drug particles. SC-CO2 milling was conducted and its performance was compared with the ones by various milling methods such as jet milling, dry milling and wet milling. A comparison on the effect of each milling medium on its milling performance, drug size distribution, and particle morphology was conducted. Operating variables of the SC-CO2 milling system were also investigated to clarify the factors affecting the milling properties and to improve drug release characteristics of water-poorly soluble drugs.

Simple and rapid synthesis of magnetite/hydroxyapatite composites for hyperthermia treatments via a mechanochemical route.

This paper presents a simple method for the rapid synthesis of magnetite/hydroxyapatite composite particles. In this method, superparamagnetic magnetite nanoparticles are first synthesized by coprecipitation using ferrous chloride and ferric chloride. Immediately following the synthesis, carbonate-substituted (B-type) hydroxyapatite particles are mechanochemically synthesized by wet milling dicalcium phosphate dihydrate and calcium carbonate in a dispersed suspension of magnetite nanoparticles, during which the magnetite nanoparticles are incorporated into the hydroxyapatite matrix. We observed that the resultant magnetite/hydroxyapatite composites possessed a homogeneous dispersion of magnetite nanoparticles, characterized by an absence of large aggregates. When this material was subjected to an alternating magnetic field, the heat generated increased with increasing magnetite concentration. For a magnetite concentration of 30 mass%, a temperature increase greater than 20 K was achieved in less than 50 s. These results suggest that our composites exhibit good hyperthermia properties and are promising candidates for hyperthermia treatments.

In-die evaluation of capping tendency of pharmaceutical tablets using force-displacement curve and stress relaxation parameter.

A novel in-die evaluation method of tablet capping tendency was proposed based on a force-displacement curve and stress relaxation parameter in a tableting process. In our previous study (Chem. Pharm. Bull., 59, 2011, Nakamura et al.), the phase diagram consisting of elastic recovery energy (E(e)) and plastic deformation energy (E(p)) of compressed powder, named as the E(e)-E(p) diagram, was proposed. However, it was found that capping tendency of tablets prepared by double-compression with multi-component powder formulations cannot be discriminated using the E(e)-E(p) diagram. To improve the capping discrimination ability, we here proposed a novel corrected phase diagram consisting of the E(e) and an interparticle bonding parameter E(b)(t), named as the E(e)-E(b)(t) diagram. The E(b)(t) was proposed as a new parameter expressing strength of the interparticle bonding formed by the stress relaxation inside compressed powder. The E(b)(t) was defined as a product of the E(p) and the stress relaxation parameter Y(t), estimated from the force-displacement curve and the stress relaxation test. The capping discrimination ability of the diagrams was evaluated using a hierarchical-clustering analysis. The results exhibited that the capping tendency could be clearly discriminated using the proposed E(e)-E(b)(t) diagram at the double-compression and the multi-component powder formulations, as compared to the E(e)-E(p) diagram. This proposed diagram can be used for screening of the powder formulations to avoid the capping.

Continuous measurement of die wall pressure in a rotary tablet machine.

In the pharmaceutical industry, tablets are manufactured using rotary tableting machines. Recently, die wall pressure in a single-punch press was measured to understand the compaction mechanism and predict tableting failure. However, die wall pressure measurements in rotary tableting machines have not been studied. Two challenges exist in measuring die wall pressure in these machines, viz. (i) lack of space inside the machine to set up the measurement equipment and (ii) difficulty in installing wired measurement hardware because the die rotates with the rotary plate. This study aimed to continuously measure die wall pressure in a rotary tableting machine and investigate the effect of high compression speed on die wall pressure. Die wall pressure at tableting speeds of up to 140 mm/s was successfully determined using a wireless telemeter. Residual die wall pressure for plastic materials was strongly dependent on the tableting speed, although the tableting speed affected the maximum die wall pressure minimally. This novel measurement technique can be used to study the effect of tableting speed on die wall pressure, which can be applied in solving the problems of capping and lamination during tablet production.

Development of a novel tablet machine for a tiny amount of powder and evaluation of capping tendency.

A novel single punch tablet machine was developed for a tiny amount of powder sample. This tablet machine mainly consists of upper and lower punches, single die, and conical powder feeder equipped with micro-vibrators. By using the powder feeder, mass of discharged powder can be maintained constant even if a tiny amount of powder having poor flowability is used. Motions of both upper and lower punches can be set arbitrarily. Thus, this machine enables us to prepare tablets with a tiny amount of powder sample under the same compression mechanism as conventional rotary tablet machines. Performance of the developed tablet machine was evaluated in a continuous direct tableting using a model powder with poor flowability. Thirty-four tablets (195 mg×34) having acceptable properties can be successfully prepared using no more than 10.0 g of a powder sample. We then proposed a novel in-die evaluation method of capping tendency. A new phase diagram consisting of the elastic recovery energy and the plastic deformation energy was proposed. These energies were calculated from a force-displacement profile, continuously monitored by the developed tablet machine. The results indicate that by using the new diagram the capping tendency of tablets prepared from various model powders can be well discriminated. The developed tablet machine and proposed evaluation method can contribute to a significant cost reduction and speeding up of formulation studies of oral dosage form.

Numerical study for tableting process in consideration of compression speed.

A numerical study of the tableting process using a finite element method (FEM) is important to quantitatively understand the structural change inside the tablet and the mechanism of tableting failures such as capping, picking, lamination, and sticking. In the pharmaceutical field, the Drucker-Prager Cap (DPC) model is used most widely to demonstrate the mechanical behavior of the powder during tableting. The DPC model, however, cannot consider compaction speed, although the compaction speed has a large impact on the tablet strength and tableting failures. In the present study, a combined novel model using both the DPC and Perzyna models, which incorporates a visco-plastic behavior considering the compression speed, was proposed and numerical simulation was conducted. Cellulose, lactose, and acetaminophen were selected as model powders. The DPC-Perzyna model parameters were determined from experimental compaction tests, unconfined compression tests, and tension tests. The calculated loading curves agreed with the experimental data under different compaction speeds, in addition the high compression speed resulted in less plastic deformation and much residual stress. It was demonstrated that the DPC-Perzyna model proposed in the present study was useful to analyze the tableting process when considering compression speed.

Improvement of dissolution property of poorly water-soluble drug by supercritical freeze granulation.

The dissolution property of the poorly water-soluble drug, flurbiprofen (FP) was improved by a novel supercritical freeze granulation using supercritical carbon dioxide. Supercritical freeze granulation was defined as a production method of the granulated substances by using the dry ice to generate intentionally for the rapid atomization of the supercritical carbon dioxide to the atmospheric pressure. This process utilized a rapid expansion of supercritical solutions (RESS) process with the mixture of the drug and lactose. In the supercritical freeze granulation, needle-like FP fine particles were obtained which adhered to the surface of lactose particles, which did not dissolve in supercritical carbon dioxide. The number of FP particles that adhered to the surface of particles decreased with an increase in the ratio of lactose added, leading to markedly improve the dissolution rate. This improvement was caused not only by the increase in the specific surface area but also the improvement of the dispersibility of FP in water. It is thus concluded that the supercritical freeze granulation is a useful technique to improve the dissolution property of the poorly water-soluble flurbiprofen.